The present invention relates to a method for generating cells with specific functions. In particular, the present invention relates to a method for generating immunomodulatory cells.
Autoimmune diseases arise from an inappropriate immune response of the body against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. Rejection of transplantation is another problem caused by undesired immune response. Transplantation is the act of transferring cells, tissues or organs from one site to another. As transplantation becomes a routine medical treatment, the immune system remains the most formidable barrier.
Immune suppression drugs are generally applied for treatment/prevention of autoimmune diseases and transplantation rejection, which decrease the immune response. Immune suppression drug companies disclose various side effects, including suppressing the whole immune system and rendering the patient susceptible to infection. Biological agents are also applied to said treatment, including anti-cytokine therapy, T cell depletion therapy, B cell depletion therapy and tolerance induction therapy. Recently, cell therapy including providing adoptive T-cell or stem cell presents a new choice for treatment/prevention of autoimmune diseases and transplantation rejection but it is still developing.
Human mesenchymal stem cells (MSCs) are a population of multilineage progenitor cells with the ability to differentiate into multiple mesenchymal lineages. MSCs have been isolated from bone marrow (BM) and a number of other organs including adipose tissue, placenta, amniotic fluid, and fetal tissues such as fetal lung and blood. The ease of isolation along with reports of differentiation into extra-mesodermal cell types have made these post-natal progenitors a popular choice for cell therapy for a variety of diseases.
In addition to multilineage differentiation capacity, BM and fetal MSCs have been shown to harbor immunomodulatory effects. MSCs have been implicated in modulating the proliferative capacity and effector functions of T cells, B cells, monocyte-derived dendritic cells (DCs) and natural killer lymphocytes (NKs). The effects of human MSCs on immune cells are mainly mediated through cell contact-independent processes, however, the precise mechanisms are still unknown.
Research is increasingly showing the importance of immunomodulatory immune cells. A number of leukocyte subpopulations are now known to exert immunosuppressive effects, including regulatory T lymphocytes, type II macrophages, and immature DCs. Data regarding immunomodulatory monocytes, on the other hand, have been scarce.
Hepatocyte growth factor (HGF) is a well-known mitogen and a developmentally important molecule. Also known as scatter factor, HGF not only imparts strong growth signals but also induces cells to migrate; hence, HGF has been well studied in the context of cancer growth and metastasis. Less is known about its non-mitogenic effects. HGF is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, and also upon haemopoietic progenitor cells. It has been shown to have a major role in embryonic organ development, in adult organ regeneration and in wound healing. It has been reported that a role for HGF and TGF-β as mediators for suppression of T-cell proliferation in a mixed lymphocyte reaction, which is proved by providing neutralizing antibodies against TGF-β and HGF, then the proliferative response of T cell being restored (Di Nicola et al., Blood 2002; 99:3838-3843). However, a different conclusion has been reported that these factors are unrelated to the suppressive effect by MSCs on T cells stimulated with mitogens and different mechanisms depending on the stimuli are suggested (Le Blanc et al., Scand J Immunol 2004; 60:307-315; Rasmusson I et al., Exp Cell Res 2005; 305:33-41). Accordingly, the functions and interactions between HGF and immune system are still unclear.